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Outsourcing partners are ready to fill the market need for greater cell therapies capacities.
As cell and gene therapies continue to grow as novel treatments for unmet medical needs, biopharmaceutical companies will need to assess their options for meeting production demand. Two categories of cell therapies represent different production processes: autologous products use the patient’s own cells, and allogeneic products are manufactured using tissue from a healthy donor.
BioPharm International spoke with Joe Codamo, PhD, head of Global Cell Therapy Business, Catalent, and Jose Cruz, director of Vector Manufacturing at Genezen, about the challenges of scaling up the production of cell therapies and ensuring capacity is met.
BioPharm: What are the specific needs for scaling up commercial production of cell therapies?
Codamo (Catalent): Autologous and allogeneic therapies are at various stages of their product lifecycles, with some shared and some unique manufacturing needs. The starting material for autologous products can be highly variable given the disease state of the patient. The ‘vein-to-vein’ process lead time is critical, so the manufacturing, product testing, and release timelines should be compatible. For allogeneic therapies, the scale-up and generation of a reproducible cell expansion process is key, as well as robust formulation and high-throughput fill/finish capacity. Shared needs include implementing a secure, robust supply chain that can support the necessary scale, throughput, and reproducibility needed once a product has been commercialized. The associated cost of goods must be appropriate, especially as some may become second- or even first-line treatments.
Cruz (Genezen): There are several challenges that all developers can expect to face when scaling up cell therapies to commercial production. A key need is to manage variability seen in development data that can be magnified upon scale-up. A structured quality-by-design (QbD) development approach fit to transition into commercial manufacturing upon regulatory approval will also need to be implemented. With increasing IND [investigational new drug] applications for novel and innovative cell therapies, it is likely that existing processes will not easily fit to new projects. It is therefore essential that critical core technologies are developed in a way to allow quick tailoring to these specialized processes.
BioPharm: Are there specific concerns regarding capacity for cell therapies?
Cruz (Genezen): The upsurge of IND applications in the cell therapy space has led to an increasingly crowded pipeline. Cell manufacturing technologies are typically very specialized, as opposed to ‘one-size-fits-all,’ resulting in further capacity challenges due to the requirement for highly customized processes.
It is essential that pharmaceutical companies can quickly and thoroughly characterize and release vector technologies. This will enable generation of qualified data that can sustain a candidate through clinical trials, as well as supporting the transition into commercial manufacturing. However, increasingly crowded pipelines can impede these processes.
With cell therapies using autologous (patient) cells specifically, such as CAR [chimeric antigen receptor] therapies, we see a need to ensure sufficient physical capacity to manage the different cells for facility processing. This is due to the requirement for isolation and separate cleanrooms when working with patients’ cells for clinical trials.
This work is predominantly manual, but there are self-contained systems available; there are moves towards automating transduction and expansion of patient’s cells in the future.
Codamo (Catalent): As the number of cell therapies in the clinical pipeline grows and more reach later-phase studies, demand for late-stage and commercial-scale manufacturing is growing correspondingly. This demand will only increase as market acceptance expands and cell therapies are potentially introduced at earlier stages of a patient’s treatment. The CDMO [contract development and manufacturing organization] industry has taken steps to help address the growing demand, as evidenced by the significant number of acquisition and expansion announcements in manufacturing capacity made over the past few years. Getting new facilities online, staffing with appropriately experienced scientific and technical personnel, and having a robust supply chain to meet the markets’ needs are concerns for all advanced therapies, including cell-based ones.
BioPharm:What are the steps for ensuring a contract partner has the capacity to manufacture cell therapies to commercial scale?
Codamo (Catalent): When evaluating a potential manufacturing partner, it is important to understand what its scale-up strategy is. For example, has it designed or optimized its infrastructure to deliver larger-scale and/or higher throughput, and is it working with its own supply chain to help assure high-quality production and consistent material quality? CDMOs should have a clear technical transfer and ramp-up strategy to go from clinical to commercial manufacturing. This [strategy] includes a process validation strategy and the supportive studies to demonstrate process and analytical robustness. Finally, the CDMO should have a global strategy to prepare for, and support, commercial launch, including topics spanning communication with regulatory authorities to a robust strategy for business continuity (staffing, material contingency, facility operations, etc.).
Cruz (Genezen): One of the biggest concerns highlighted by clients is the need to find a CDMO offering both the roadmap to commercially manufacture cell therapies as well as the technical skill set to solve the inevitable challenges along the way. Selecting a partner with future commercial capacity while demonstrating cross-industry experience in the clinic, regulatory, and manufacturing sciences is key to successful commercialization, but they can be difficult to find.
Once a suitable partner is identified, early engagement between developers and the technical team is needed to develop a ‘best-launch’ process with an overarching aim to create a ‘best-in-class’ scope of work.
BioPharm: What are the benefits of outsourcing the production of cell therapies?
Cruz (Genezen): Outsourcing cell therapy production has many benefits, particularly for smaller and younger companies with limited financial capital aiming to minimize the fixed costs that can be associated with building physical infrastructure.
Working with a dedicated CDMO partner also provides access to cross-functional expertise from process development, manufacturing sciences, operations, engineering, quality assurance, and regulatory. The seasoned expertise offered by CDMOs can act to bridge the path between discovery and clinical, as well as development and commercial manufacturing.
Working with CDMOs that have standardized development processes
built on QbD principles while offering tailored-fit technologies to manage inherent variability of cell processes will also help to increase speed to market.
Codamo (Catalent): An outsourced manufacturing partner can offer scalability, quality, and the regulatory experience gained from producing a variety of products and modalities. A CDMO provides opportunities for supply-chain streamlining and the leveraging of strong, global supply arrangements, as well as the necessary manufacturing capacity to help an early-stage cell therapy company ready itself for production within fast-paced timelines. CDMOs that can support end-to-end services including starting materials (plasmid DNA, viral vectors) and clinical logistics can simplify the supply chain. Outsourcing allows companies to avoid investing in CGMP [current good manufacturing practice] facilities, which may not be cost effective, and pose a financial risk when product demand and its clinical or market success
BioPharm: What are the challenges of outsourcing cell therapy production?
Codamo (Catalent): These can include the management of timelines and communication with manufacturing partners, especially if multiple partners are involved in the process. Gene-enabled cell therapies require viral vector manufacturing as well as the production of the final product, and manufacturing of the cell therapy cannot begin until the viral vector is available. The cell therapy company may need to manage the communication between the CDMOs and their timelines, or if using a single manufacturing partner with integrated services, ensure that the partner provides one main point of contact and streamlines the integration between the supply chain stages.
Cruz (Genezen): As well as the challenge of identifying a CDMO offering both expertise and capacity, it is also necessary to ensure the availability of this capacity in the required timeframe and availability of analytical technologies.
These analytical methods include master cell bank (MCB) and vector product release testing, RCL assays, HEK293T host cell protein (HCP) assays, and others that are essential in determining quality at different stages of the process.
Developers looking for a CDMO partner should also consider whether they are looking for a short or long-term investment. If they envisage the project scaling up from discovery to clinical supply and then to commercial manufacturing, they must determine whether they wish to eventually bring specific steps in-house. If aiming to bring the product to market with support from a CDMO, they should determine whether their partners have these capabilities early in the project’s lifetime to ease transitions and avoid delays.
BioPharm: What is the ratio of in-house vs. outsourced production of cell therapies? Do you see the industry increasing the amount of outsourcing for these therapies?
Codamo (Catalent): For small-scale needs, such as in the early-phase studies, we estimate that more in-house production is currently conducted. However, once either larger batch sizes are needed, or a wider distribution of manufacturing is necessary, the ratio of in-house to outsourced manufacturing changes. Outsourcing partners with established clinical supply capabilities as well as manufacturing expertise are better suited to manage larger scale or larger numbers of batches and the vein-to-vein logistics. For those with in-house capabilities, there is the potential for secondary and back-up supplies to be provided from outsourcing partners as therapies receive worldwide approval.
Cruz (Genezen): Currently, the ratio of in-house to outsourced viral vector manufacturing is around 40:60 with lentiviral vector and adeno-associated viral vector manufacturing constituting 66% of total projects (1). Outsourcing is expected to further increase to 68% in the next five years.
Cell therapies using allogeneic (donor) cells, as opposed to autologous cells, could drive greater outsourcing. As managing or handling autologous cells is a critical step, companies are often keen to keep this process in-house. Unlike autologous cells, allogeneic cells have the potential to be produced in one large batch before being packaged into individual doses. Although less personalized, these therapies require processes that are much more manageable at large scale as compared with autologous cell handling and may be more suited to outsourcing.
1. E. Harris, “A Summary of Cell & Gene Therapies Market Outlook Report,” Cell & Gene, Feb. 7, 2022.